CN1134151A - Pyrazine carboxamide derivs., their production and their use in medicaments - Google Patents
Pyrazine carboxamide derivs., their production and their use in medicaments Download PDFInfo
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- CN1134151A CN1134151A CN94194016A CN94194016A CN1134151A CN 1134151 A CN1134151 A CN 1134151A CN 94194016 A CN94194016 A CN 94194016A CN 94194016 A CN94194016 A CN 94194016A CN 1134151 A CN1134151 A CN 1134151A
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- 0 C*(CC1)CCN1C1=NC(*=C)=CN2C(*)=CN(C)C12 Chemical compound C*(CC1)CCN1C1=NC(*=C)=CN2C(*)=CN(C)C12 0.000 description 1
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- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
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- A61P9/12—Antihypertensives
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Abstract
New compounds of general formula (I) are provided which are explained in the specification can be prepared by a variety of methods. The compounds may be used in pharmaceutical compositions.
Description
The present invention relates to pyrazinecarboxamide derivatives, its preparation method and the application aspect its pharmaceutical compositions.
One aspect of the present invention provides formula (I) compound and acid salt thereof
Wherein A represents to be connected in by nitrogen-atoms the following radicals of Zinamide system :-C
mH
2m-NR
4--C
mH
2m-NR
4-C
pH
2p-NR
4The NR of '--
4-C
mH
2m-NR
4'
R
1Expression hydrogen, fluorine, chlorine, C
1-4-alkyl, C
3-7Cycloalkyl, C
1-4-alkoxyl group, trifluoromethyl, phenyl, benzyl, phenyl-low alkyl group, phenyl-low-grade alkenyl, phenyl-low-grade alkynyl or phenoxy group, wherein phenyl can contain at the most 3 and is selected from C
1-4-alkyl, C
1-4-alkoxyl group, CF
3, F, Cl or CN substituting group; R
2Expression following formula group
R wherein
3, R
4And R
4' can be identical or different, expression hydrogen or C
1-4-alkyl, or R
4Or R
4' also can represent phenyl, benzyl or C
3-7-cycloalkyl; R
5And R
6Can be identical or different, expression hydrogen, methyl, methoxyl group, hydroxyl or halogen; R
7Expression hydrogen, C
1-4-alkyl, benzyl or benzyloxy; R
8And R
9Identical or different, expression hydrogen, C
1-4-alkyl, phenyl or halogen; R
10Expression hydrogen or C
1-6-alkyl, it also can by phenyl or methyl-, methoxyl group-or the phenyl of halogen-replacement replace; R
11And R
12Can be identical or different, expression hydrogen, methyl, methoxyl group, phenyl, benzyl, nitro, cyano group, halogen, trifluoromethyl, amino, NR
10R
13, 1-pyrrolidyl, 1-pyrazolinyl, 1-tetrahydroglyoxaline, piperidino, 1-piperazinyl or formamyl, and R
11Also can represent to contain at the most 3 and be selected from methyl, methoxyl group, halogen, CF
3Substituent fused benzene rings with CN; R
13Expression hydrogen, halogen or C
1-4-alkyl, it also can be replaced by phenyl, phenoxy group or benzyloxy; Reaching E and G can be identical or different, expression N or CH; M represents 2,3,4,5 or 6, n represent 0 or 1 and p represent 2,3 or 4.
Alkyl in above-mentioned definition, alkenyl, alkynyl or alkylidene group can be straight or branched.Term " rudimentary " is meant to have 1-4, and particularly 1-3 is individual, more especially 1-2 carbon atom.Halogen is meant fluorine, chlorine and bromine, and fluorine and chlorine are particularly preferred.Preferred unsaturated alkyl is meant allyl group and propargyl.Letter m preferably represents 2,3 or 4, and p preferably represents 2 or 3.
This new compound can be different steric isomer or the form of suitable/anti--isomer exist, top general formula is represented its pure form and its mixture.The present invention includes all steric isomers or suitable/anti--isomeric forms, no matter it is optically pure or exists with its form of mixtures.
The typical R of the structure shown in below having
2-A-group is representational:
And, if A is connected to R by nitrogen-atoms
2On the group, group A exists usually so, wherein, and R
2Lian Jian is from carbon atom, suc as formula (II '), shown in (III ') and (IV ').
Can prepare this new compound by several different methods, these methods constituted of the present invention in addition-aspect.These methods comprise known several different methods itself.
The example of the inventive method is following a) to make following formula: compound
React with following formula amine
R
2-A-H (XVII) wherein, R
1And R
2Definition as above;
This reaction is carried out in water-free polar solvent or its mixture, is meant methyl-sulphoxide, dimethyl formamide especially, preferably carries out under the condition that is heating up in the presence of alkali such as triethylamine, N-methyl piperidine, the pyridine.
B) in order to prepare wherein R
2Be formula (I) compound of formula II, formula III or formula IV, can pass through radicals R
2Another nitrogen-atoms connect.For example, R wherein
2The compound of expression II group can be by making general formula X VIII acid amides (wherein A ' expression is connected to R by nitrogen-atoms
2The A group, suc as formula II ', III ' and IV ') (R wherein
1Definition as above)
Synthetic with the quinazoline derivant reaction
What adopt is that the described step c) of step (a) makes following formula: compound
Wherein R represents low alkyl group or benzyl and R
1, R
2React with guanidine as mentioned above with the definition of A.
In reaction (c), reaction not only is confined to wherein R ester as defined above, just those skilled in the art should very ten thousand adopt the ester that is easy to prepare, as methyl esters or ethyl ester, or refers to the ester that the alcohol that obtains does not have problems when not influencing reaction or generation from ester.
The preferred alcohol that also contains in ester that uses for example makes the methyl ester of formula XX react in methyl alcohol under its boiling point as solvent in the reaction.This-method is best suited in the preparation The compounds of this invention.
When formula (I) compound is when occurring with steric isomer or other isomeric form, should adopt corresponding starting raw material.Perhaps, may in preparation process, form through separating the mixture can obtain each component.
Unknown starting raw material also can obtain by ordinary method, and for example, the N-amidino groups-methane amide with corresponding ester replacement formula XVI or XVII obtains formula XIX starting raw material.
Active substance in the formula I compound useful as drug composition, or as the intermediate for preparing these active substances.Here, new compound suppresses Na
+/ H
+-and Na
+/ Li
+-exchange.The compounds of this invention can be used as hypotensive agent, mucolytic agent, diuretic(s) and cancer stablizer (cancerostatics); They also can be used for treatment and local asphyxia diseases associated (for example the local asphyxia of heart, brain, gi tract, lung and kidney, liver local asphyxia, or the local asphyxia of whole-body muscle system).Corresponding disease comprises, for example the embolism in coronary heart disease, chest angina, the pulmonary circulation, acute or chronic renal failure, renal insufficiency, cerebral thrombosis are (for example with t-PA, bonded such as streptokinase, urokinase, the thrombus that after thrombus is opened, occurs after the recirculation of blood by brain), the acute and chronic circulatory disorders of brain.In order to compensate ischemic heart (for example after stenocardia or myocardial infarction outbreak), myocardial cell's irreversible damage appears in affected zone.In addition, The compounds of this invention is used in particular for Cardioprotective in these cases.The superiority of new compound is the side effect that it is minimum, and it is noticeable especially that α 1-and/or α 2-effect essence do not exist.
About ischemic Application Areas also comprises for the protection of transplanting associated injury (for example in migration process and transplant afterwards protection to transplant organ).
Active substance can be used by regular dosage form, the tablet of regular dosage form such as conventional tablet or coating, capsule, granula, injection liquid or if possible, the preparation of nasal administration.The content of active substance of per unit dosage is 1-200mg normally, preferred 20-100mg.The pharmaceutical composition that contains with the physiologically acceptable carrier of The compounds of this invention bonded, thinner or vehicle has constituted another aspect of the present invention content.
These pharmaceutical dosage forms can prepare according to known method, and by following non-limiting example explanation.
Medicine embodiment
1, tablet (composition)
Embodiment compound 40.0mg
W-Gum 144.0mg
Sec calcium phosphate 115.0mg
Magnesium Stearate 1.0mg
300mg
2, gelatine capsule
Capsule is made up of the beautiful starch of the The compounds of this invention of 50.0mg and 150.0mg.
Following synthetic embodiment has illustrated an aspect of of the present present invention content.
* embodiment 1 (method is N-[2-(6,7-dimethoxy-4 '-quinazolyl)-N '-[5-[2-(N-amidino groups-formamyl)-3-amino-6-chlorine] pyrazinyl a)]-N, N piperazine-hydrochloride
Make the 3-amino-5 of 285.5mg (1mmol); 6-dichloropyrazine acyl group-2-guanidine-hydrochloride and 326.8mg 3-piperazinyl-(6; 7-dimethoxy-quinazoline-4-yl) hydrochloride in the 10ml dimethyl formamide, in the presence of the 100mg triethylamine, heated 2 hours to 90-100 ℃ together.
Behind the cool to room temperature, the product of filtering for crystallizing obtains the 480mg reaction product.Product is suspended in the 5ml methyl alcohol, and adds methanolic hydrochloric acid to generate corresponding hydrochloride.Add 2.5ml water temperature heat (warning up) and obtain clear soln, therefrom obtain the title compound of 350mg after the cooling, fusing point 260-263 ℃.
Embodiment 2N-[2-(4-amino-6,7-dimethoxy) quinazolyl]-N '-[5-[2-(N-amidino groups-formamyl)-3-amino-6-chlorine] pyrazinyl]-N, N '-dimethyl-1-hydrochloride
* a) make 7.2g (30mmol) 1-amino-3-chloro-6, the 7-dimethoxyquinazoline, 13.2g (150mmol) N, N '-dimethyl-ethylenediamine refluxed 1 hour in the 60ml Pentyl alcohol, and steaming desolventizes and residue is dissolved in the 100ml acetonitrile solution then, filters.Crystallize out by crude product in the middle of the cooling reaction 6.05g, again it is dissolved in the water that 60ml refluxes, add recrystallized product behind the 80ml, separate the pure N-[(4-amino-6 that obtains 3.9g, the 7-dimethoxy)-the 2-quinazolyl]-N, N '-dimethyl-1.B) with the N-[(4-amino-6 of 5.83 (20mmol), the 7-dimethoxy)-the 2-quinazolyl]-N, N '-dimethyl-1, the 2-diaminoethanes, 4.44g 3-amino-5 (20mmol), the triethylamine of 6-dichloropyrazine-2-carboxylate methyl ester and 2.75ml (20mmol) is dissolved in the 30ml methyl-sulphoxide, and under agitation heats 2 hours to 80 ℃.After the cooling, add 60ml water, by the reaction product of suction strainer precipitation separation.After the drying, need not be further purified and make material (product 9.1g) reaction that obtains, prepare guanidine derivative.C) under the room temperature, 9.07g (95mmol) guanidine-hydrochloride was stirred 30 minutes in the sodium methoxide solution of 95ml (95mmol) 1N methanolizing, remove the sodium-chlor precipitation by suction strainer.Make filtrate and 9.1g (19.1mmol) 3-amino-6-chloro-5-[2-[(4-amino-6, the 7-dimethoxy)-the 2-quinazolyl]-1-(N, N '-dimethyl-1, the 2-diamino ethyl)]-pyrazine-2-carboxylate methyl ester mixed 100-110 ℃ of heating 3 hours that are incorporated in the 50ml dimethyl formamide, the residue that obtains after steaming desolventizes purifying on silicagel column, eluent: ethyl acetate 70/ Virahol 30/NH
4OH 10. is dissolved in ethanol also with the hcl acidifying in the ether, by adding the ether crystalline hydrochloride with the material behind the purifying.Productive rate 5.4g, fusing point 227-230 ℃.
Compound listed in the following table can prepare according to the data of the foregoing description and/or specification sheets.
Table 1
R wherein
2-A is the formula Ia compound N o. m R of formula II ' group
4R
4Mp.[℃] 12 H H>2,202 2 CH
3H3 2 H CH
342 CH
3CH
3227-305 2 CH
3C
2H
562 C
2H
5CH
372 C
2H
5C
2H
582 i-C
3H
7CH
392 CH
3I-C
3H
710 2 i-C
3H
7I-C
3H
711 3 H CH
312 3 CH
3H13 3 CH
3CH
314 3 C
2H
5CH
315 3 CH
3C
2H
516 3 C
2H
5C
2H
517 3 i-C
3H
7CH
318 3 CH
3I-C
3H
719 3 i-C
3H
7I-C
3H
720 6 CH
3CH
3190-221 3 n-C
4H
9N-C
4H
9
Table 2
R wherein
2-A is the formula Ia compound N o. R of formula III ' group
4' R
4Configuration Mp.[℃] 1 H H cis, 2 CH
3H cis 3 H CH
3Cis 4 CH
3CH
3Cis 5 n-C
3H
7N-C
3H
7Cis 6 H H trans 7 CH
3H trans 8 H CH
3Trans 9 CH
3CH
3Trans10 n-C
3H
7N-C
3H
7Trans11 i-C
4H
9H cis/trans12 H t-C
4H
9Cis/trans
Annotate: cis is a cis, and trans is trans
Table 3
R wherein
2-A is the formula Ia compound N o. m n R of formula VI ' group
4Mp.[℃] 120 H, 220 CH
3320 C
2H
5420 i-C
3H
7520 C
6H
5621 H, 721 CH
3821 C
2H
5921 i-C
3H
710 21 C
6H
511 30 H12,30 CH
313 30 C
2H
514 30 i-C
3H
715 30 C
6H
516 31 H17,31 CH
318 31 C
2H
519 31 i-C
3H
720 31 C
6H
5
Table 4
R wherein
2-A is formula V ' group, R
3Be that hydrogen and p are 2 formula Ia compound N o. m R
4' R
4Mp.[℃] 12 H H, 22 CH
3CH
332 C
2H
5C
2H
542 i-C
3H
7I-C
3H
752 C
6H
5CH
363 H H, 73 CH
3CH
383 C
2H
5C
2H
593 i-C
3H
7I-C
3H
710 3 C
6H
5CH
311 2 n-C
4H
9CH
312 2 C
6H
5C
6H
5
Table 5
R wherein
2-A is the formula Ia compound N o. m R of formula VI ' group
4R
3Mp.[℃] 12 H H, 22 CH
3CH
332 C
2H
5C
2H
542 i-C
3H
7I-C
3H
752 C
6H
5CH
363 H H, 73 CH
3CH
383 C
2H
5C
2H
593 i-C
3H
7I-C
3H
710 3 C
6H
5CH
311 2 n-C
4H
9CH
312 2 C
6H
5C
6H
5
Table 6
R wherein
2The formula Ia compound of-A expression VII ' group
No. R
8R
9Mp.[℃] 1 H H2 CH
3Cl3 Cl Cl4 CH
3CH
3
Table 7
R wherein
2The formula Ia compound of-A expression VIII ' group
No. R
9Mp.[℃] 1 H2 Cl3 CH
3
Table 8
R wherein
2The formula Ia compound (R of-A expression IX ' group
11/ R
12
The location is for phenyl) No. R
10R
11R
12Mp.[℃] 1 H H H, 2 H 3-Cl H, 3 H 2-F 3-F, 4 H 4-NO
2H 5 H 4-CN H 6 H 3-OCH
34-OCH
37 H CH
3H 8 H 4-F 3-C
2H
59 H 4-CH
2-C
6H
5H10 H 4-OCH
32-CH
2-C
6H
511 CH
3H H12 CH
33-Cl H13 CH
32-F 3-F14 CH
34-NO
2H15 CH
34-CN H16 CH
33-OCH
34-OCH
317 CH
3CH
3H18 CH
34-F 3-C
2H
519 CH
34-CH
2C
6H
5H20 CH
34-OCH
32-CH
2-C
6H
521 C
2H
5H H22 C
2H
53-Cl H23 C
2H
52-F 3-F24 C
2H
54-NO
2HNo. R
10R
11R
12Mp.[℃] 25 C
2H
54-CN H26 C
2H
53-OCH
34-OCH
327 C
2H
5CH
3H28 C
2H
54-F 3-C
2H
529 C
2H
54-CH
2C
6H
5H30 C
2H
54-OCH
32-CH
2-C
6H
531 i-C
3H
7H H32 n-C
6H
134-F H33 4-F-C
6H
44-F H34 CH
2-C
6H
54-F H35 C
2H
54-F H36 n-C
4H
92-CH
36-CH
3
Table 9
R wherein
2The formula Ia compound of-A expression X ' group
(R
3And R
9Expression H) No. R
8R
13Mp.[℃] 1 H H2 C
2H
5H3 H CH
34 i-C
3H
7H5 H CH
36 H Br7 Br H8 CH
3H
Table 9a
R wherein
2The formula Ia compound of-A expression X ' group
(R
3And R
9Expression H) No. R
8R
13Mp.[℃] 1 H H2 C
2H
5H3 H CH
34 i-C
3H
7H5 i-C
3H
7CH
36 H Br7 Br H8 CH
3H
Table 10
R wherein
2The formula Ia compound of-A expression XI ' group
No. R
11R
12Mp.[℃] 1 NH
2H 275-82 CONH
2H3 Cl H4 Cl Cl5 H H 288-906 H CH
37 CH
3H8 CN H 239-419 CH
3CH
3
Table 11
R wherein
2The formula Ia compound of-A expression XII ' or XIII ' group
R wherein
14And R
15Represent radicals R respectively
3And R
4, but also can represent jointly-CH
2-CH
2-CH
2-CH
2-No. R
14R
15Form Mp.[℃] 1 H CH
32 CH
3H 3 CH
3CH
3Along 4 CH
3CH
3Anti-5 C
2H
5CH
3Suitable/anti-6 C
2H
5C
2H
5Along 7 C
2H
5C
2H
5Anti-8 H H x2HCl 295-310 (D), 9 H i-C
3H
710-CH
2-CH
2-CH
2-CH
2-along 11-CH
2-CH
2-CH
2-CH
2-anti-
Table 12
R wherein
2The formula Ia compound of-A expression XIV ' group, R
5And R
6The location be No. R for the quinazolinone ring system
7R
5R
6Mp.[℃] 1 H H H 260-3,2 H 6-OCH
37-OCH
33 H 8-OCH
3H 4 H 6-OH 7-OH 5 H 7-OH H 6 H 8-OH H 7 H 6-Cl H 8 H 6-CH
37-CH
39 CH
3H H10 CH
36-OCH
37-OCH
311 CH
38-OCH
3H12 CH
36-OH 7-OH13 CH
37-OH H14 CH
38-OH H15 CH
36-Cl H16 CH
36-CH
37-CH
3
Table 13
R wherein
2The formula Ia compound N o. m R of-A expression XV ' group
3Mp.[C] 12 H 260-262,22 CH
332 H, 42 CH
352 n-C
4H
962 H, 73 H, 83 CH
393 H10,3 CH
311 3 n-C
4H
912 3 H
Table 14
Table 15
R
2The formula Ia compound that is defined as follows for formula III ' group and A
Claims (8)
1, formula (I) compound and acid salt thereof, with and single steric isomer or suitable/anti--isomer and/or these mixture of isomers:
Wherein A represents to be connected in by nitrogen-atoms the following radicals of Zinamide system :-C
mH
2m-NR
4-,-C
mH
2m-NR
4-C
pH
2p-NR
4'-,
-NR
4-C
mH
2m-NR
4'-
R
1Expression hydrogen, fluorine, chlorine, C
1-4-alkyl, C
3-7Cycloalkyl, C
1-4-alkoxyl group, trifluoromethyl, phenyl, benzyl, phenyl-low alkyl group, phenyl-low-grade alkenyl, phenyl-low-grade alkynyl or phenoxy group, wherein phenyl can contain at the most 3 and is selected from C
1-4-alkyl, C
1-4-alkoxyl group, CF
3, F, Cl or CN substituting group; R
2Expression following formula group
R wherein
3, R
4And R
4' can be identical or different, expression hydrogen or C
1-4-alkyl, or R
4Or R
4' also can represent phenyl, benzyl or C
3-7-cycloalkyl; R
5And R
6Can be identical or different, expression hydrogen, methyl, methoxyl group, hydroxyl or halogen; R
7Show hydrogen, C
1-4-alkyl, benzyl or benzyloxy; R
8And R
9Identical or different, expression hydrogen, C
1-4-alkyl, phenyl or halogen; R
10Expression hydrogen or C
1-6-alkyl, it also can by phenyl or methyl-, methoxyl group-or the phenyl of halogen-replacement replace; R
11And R
12Can be identical or different, expression hydrogen, methyl, methoxyl group, phenyl, benzyl, nitro, cyano group, halogen, trifluoromethyl, amino, NR
10R
13, 1-pyrrolidyl, 1-pyrazolinyl, 1-tetrahydroglyoxaline, piperidino, 1-piperazinyl or formamyl, and R
11Also can represent to contain at the most 3 and be selected from methyl, methoxyl group, halogen, CF
3Substituent fused benzene rings with CN; R
13Expression hydrogen, halogen or C
1-4-alkyl, it also can be replaced by phenyl, phenoxy group or benzyloxy; Reaching E and G can be identical or different, expression N or CH; M represents 2,3,4,5 or 6, n represent 0 or 1 and p represent 2,3 or 4.
2, the described formula of claim 1 (I) compound, wherein R
2-A expression II ' is to formula XV ' group and R
3, R
4And R
4' can be identical or different, expression hydrogen or C
1-C
3Alkyl.
3, the described formula of claim 1 (I) compound, wherein R
2Expression XI group and G or E represent N.
5, the pharmaceutical composition that contains the arbitrary described compound of claim 1-4 and physiologically acceptable thinner, vehicle and/or carrier.
6, the application of the arbitrary described compound of claim 1-4 in pharmaceutical compositions.
7, the arbitrary described compound of claim 1-4 is as hypotensive agent, mucolytic agent, diuretic(s) and cancerostatic agent; in treatment and local asphyxia diseases associated; cerebral thrombosis, acute and chronic brain circulatory diseases is at Cardioprotective with in the application that prevents to transplant aspect the infringement.
8, the method for formula (I) compound of preparation claim 1 definition, this method comprises: (a) make formula (XVI) compound
R wherein
1Definition such as the reaction of claim 1 and formula (XVII) amine
R
2-A-H (XVII) is A and R wherein
2Definition such as claim 1; Or (b) in order to prepare the wherein R of claim 1 definition
2Be formula II, formula (I) compound of formula III or formula IV makes general formula (XVIII) amine
Wherein A ' expression is connected to R by nitrogen-atoms
2A group on the carbon atom, and R
1Definition according to claim 1, react with formula (XIX) compound
Perhaps (c) makes formula (XX) compound
Wherein R represents low alkyl group or benzyl, and is necessary and/or when needing subsequently with guanidine reaction, separated product obtain its different three-dimensional form and/or arbitrarily the alkali of formula (I) change into its acid salt, maybe the salt that obtains is converted into free alkali.
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
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DEP4337609.6 | 1993-11-04 | ||
DE4337609A DE4337609A1 (en) | 1993-11-04 | 1993-11-04 | Novel pyrazinecarboxamide derivatives, their preparation and their use in medicines |
Publications (1)
Publication Number | Publication Date |
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CN1134151A true CN1134151A (en) | 1996-10-23 |
Family
ID=6501757
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
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CN94194016A Pending CN1134151A (en) | 1993-11-04 | 1994-10-31 | Pyrazine carboxamide derivs., their production and their use in medicaments |
Country Status (17)
Country | Link |
---|---|
EP (1) | EP0726899B1 (en) |
JP (1) | JPH09505035A (en) |
KR (1) | KR960705815A (en) |
CN (1) | CN1134151A (en) |
AT (1) | ATE188965T1 (en) |
AU (1) | AU690588B2 (en) |
CA (1) | CA2175837A1 (en) |
CO (1) | CO4290432A1 (en) |
DE (2) | DE4337609A1 (en) |
DK (1) | DK0726899T3 (en) |
ES (1) | ES2140565T3 (en) |
GR (1) | GR3033034T3 (en) |
NZ (1) | NZ274848A (en) |
PL (1) | PL314187A1 (en) |
PT (1) | PT726899E (en) |
WO (1) | WO1995012592A1 (en) |
ZA (1) | ZA948669B (en) |
Cited By (1)
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CN103467392A (en) * | 2013-10-09 | 2013-12-25 | 重庆工商大学 | Polyhalogenated pyrazinecarboxamide derivative and salts, preparation method and application thereof |
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DE19548812A1 (en) * | 1995-12-27 | 1997-07-03 | Hoechst Ag | Use of inhibitors of the cellular Na · + · / H · + · exchanger (NHE) for the manufacture of a medicament for respiratory stimulation |
DE19738604A1 (en) * | 1997-09-04 | 1999-03-11 | Hoechst Marion Roussel De Gmbh | Use of Na<+>/H<+> exchange inhibitors |
EP1182194A4 (en) | 1999-06-03 | 2004-02-11 | Takeda Chemical Industries Ltd | Pernasal preparations |
US6156758A (en) * | 1999-09-08 | 2000-12-05 | Isis Pharmaceuticals, Inc. | Antibacterial quinazoline compounds |
KR20050008691A (en) | 2002-04-19 | 2005-01-21 | 셀룰러 지노믹스 아이엔씨 | Imidazo[1,2-a]Pyrazin-8-ylamines Method Of Making And Method Of Use Thereof |
AU2003270489A1 (en) | 2002-09-09 | 2004-03-29 | Cellular Genomics, Inc. | 6-ARYL-IMIDAZO(1,2-a)PYRAZIN-8-YLAMINES, METHOD OF MAKING, AND METHOD OF USE THEREOF |
WO2004072081A1 (en) | 2003-02-10 | 2004-08-26 | Cellular Genomics, Inc. | Certain 8-heteroaryl-6-phenyl-imidazo[1,2-a]pyrazines as modulators of kinase activity |
US7405295B2 (en) | 2003-06-04 | 2008-07-29 | Cgi Pharmaceuticals, Inc. | Certain imidazo[1,2-a]pyrazin-8-ylamines and method of inhibition of Bruton's tyrosine kinase by such compounds |
WO2005005429A1 (en) | 2003-06-30 | 2005-01-20 | Cellular Genomics, Inc. | Certain heterocyclic substituted imidazo[1,2-a]pyrazin-8-ylamines and methods of inhibition of bruton’s tyrosine kinase by such compounds |
EP1644369A2 (en) | 2003-07-02 | 2006-04-12 | F. Hoffmann-La Roche Ag | Arylamine-substituted quinazolinone compounds |
WO2005019220A2 (en) | 2003-08-11 | 2005-03-03 | Cellular Genomics Inc. | Substituted imidazo[1,2-a]pyrazines as modulators of kinase activity |
EP1668013B1 (en) | 2003-09-23 | 2012-02-22 | Vertex Pharmaceuticals Incorporated | Pyrazolopyrrole derivatives as protein kinase inhibitors |
US7777040B2 (en) | 2005-05-03 | 2010-08-17 | Cgi Pharmaceuticals, Inc. | Certain substituted ureas, as modulators of kinase activity |
JP5496915B2 (en) | 2008-02-13 | 2014-05-21 | シージーアイ ファーマシューティカルズ,インコーポレーテッド | 6-Aryl-imidazo [1,2-a] pyrazine derivatives, methods for their preparation, and methods for their use |
HUE030427T2 (en) | 2008-12-08 | 2017-05-29 | Gilead Connecticut Inc | Imidazopyrazine Syk inhibitors |
US8450321B2 (en) | 2008-12-08 | 2013-05-28 | Gilead Connecticut, Inc. | 6-(1H-indazol-6-yl)-N-[4-(morpholin-4-yl)phenyl]imidazo-[1,2-A]pyrazin-8-amine, or a pharmaceutically acceptable salt thereof, as a SYK inhibitor |
JP5696052B2 (en) | 2008-12-08 | 2015-04-08 | ギリアード コネチカット, インコーポレイテッド | Imidazopyrazine SYK inhibitor |
NZ602362A (en) | 2010-03-11 | 2014-11-28 | Gilead Connecticut Inc | Imidazopyridines syk inhibitors |
EP2616460B1 (en) * | 2010-09-13 | 2015-10-28 | Otsuka Pharmaceutical Co., Ltd. | Heterocyclic compounds for treating or preventing disorders caused by reduced neurotransmission of serotonin, norephnephrine or dopamine. |
AP2016009007A0 (en) | 2013-07-30 | 2016-01-31 | Gilead Connecticut Inc | Formulation of syk inhibitors |
TW201602108A (en) | 2013-07-30 | 2016-01-16 | 吉李德康乃狄克公司 | Polymorph of Syk inhibitors |
PT3076976T (en) | 2013-12-04 | 2020-12-07 | Kronos Bio Inc | Methods for treating cancers |
US9290505B2 (en) | 2013-12-23 | 2016-03-22 | Gilead Sciences, Inc. | Substituted imidazo[1,2-a]pyrazines as Syk inhibitors |
UY35898A (en) | 2013-12-23 | 2015-07-31 | Gilead Sciences Inc | ? SYK INHIBITING COMPOUNDS AND COMPOSITIONS THAT UNDERSTAND THEM ?. |
KR20170029580A (en) | 2014-07-14 | 2017-03-15 | 길리애드 사이언시즈, 인코포레이티드 | Combinations for treating cancers |
KR102399996B1 (en) | 2017-08-25 | 2022-05-20 | 길리애드 사이언시즈, 인코포레이티드 | Polymorphs of SYK Inhibitors |
JP2022521413A (en) | 2019-02-22 | 2022-04-07 | クロノス バイオ インコーポレイテッド | Solid form of condensed pyrazine as a SYK inhibitor |
Family Cites Families (2)
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NL299931A (en) * | 1962-10-30 | |||
TW213903B (en) * | 1991-08-16 | 1993-10-01 | Boehringer Ingelheim Kg |
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1993
- 1993-11-04 DE DE4337609A patent/DE4337609A1/en not_active Withdrawn
-
1994
- 1994-10-31 ES ES94931018T patent/ES2140565T3/en not_active Expired - Lifetime
- 1994-10-31 WO PCT/EP1994/003580 patent/WO1995012592A1/en active IP Right Grant
- 1994-10-31 CA CA002175837A patent/CA2175837A1/en not_active Abandoned
- 1994-10-31 CN CN94194016A patent/CN1134151A/en active Pending
- 1994-10-31 PL PL94314187A patent/PL314187A1/en unknown
- 1994-10-31 DK DK94931018T patent/DK0726899T3/en active
- 1994-10-31 AT AT94931018T patent/ATE188965T1/en not_active IP Right Cessation
- 1994-10-31 EP EP94931018A patent/EP0726899B1/en not_active Expired - Lifetime
- 1994-10-31 NZ NZ274848A patent/NZ274848A/en unknown
- 1994-10-31 JP JP7513010A patent/JPH09505035A/en active Pending
- 1994-10-31 PT PT94931018T patent/PT726899E/en unknown
- 1994-10-31 AU AU79936/94A patent/AU690588B2/en not_active Ceased
- 1994-10-31 DE DE59409094T patent/DE59409094D1/en not_active Expired - Fee Related
- 1994-11-02 CO CO94050173A patent/CO4290432A1/en unknown
- 1994-11-03 ZA ZA948669A patent/ZA948669B/en unknown
-
1996
- 1996-05-03 KR KR1019960702301A patent/KR960705815A/en not_active Application Discontinuation
-
2000
- 2000-03-22 GR GR20000400720T patent/GR3033034T3/en not_active IP Right Cessation
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN103467392A (en) * | 2013-10-09 | 2013-12-25 | 重庆工商大学 | Polyhalogenated pyrazinecarboxamide derivative and salts, preparation method and application thereof |
CN103467392B (en) * | 2013-10-09 | 2016-08-17 | 重庆工商大学 | A kind of polyhalo pyrazinecarboxamide derivatives and its esters, preparation method and purposes |
Also Published As
Publication number | Publication date |
---|---|
CO4290432A1 (en) | 1996-04-17 |
WO1995012592A1 (en) | 1995-05-11 |
PT726899E (en) | 2000-04-28 |
EP0726899A1 (en) | 1996-08-21 |
KR960705815A (en) | 1996-11-08 |
AU690588B2 (en) | 1998-04-30 |
ATE188965T1 (en) | 2000-02-15 |
DK0726899T3 (en) | 2000-06-26 |
ES2140565T3 (en) | 2000-03-01 |
NZ274848A (en) | 1998-03-25 |
DE4337609A1 (en) | 1995-05-11 |
PL314187A1 (en) | 1996-09-02 |
EP0726899B1 (en) | 2000-01-19 |
JPH09505035A (en) | 1997-05-20 |
CA2175837A1 (en) | 1995-05-11 |
GR3033034T3 (en) | 2000-08-31 |
ZA948669B (en) | 1995-07-04 |
DE59409094D1 (en) | 2000-02-24 |
AU7993694A (en) | 1995-05-23 |
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